tbuckley/cabot-search huggingface dataset:
Abstract 10882: Homozygous Familial Hypercholesterolemia: Luck Meets Opportunity Meets Knowledge
Authors: Lisa Young, Emily Brown, Seth S Martin
Journal: Circulation (2022)

Introduction: Homozygous familial hypercholesterolemia (HoFH) is an inherited autosomal co-dominant disorder characterized by severely elevated circulating low-density lipoprotein (LDL). Monoclonal antibodies are now a treatment focus. Inhibition of proprotein convertase subtilisin kexin type 9 (PCSK9) increases the number of LDL receptors. Inhibition of angiopoietin-like 3 (ANGPTL3) inhibitor is associated with hypolipidemia and reduced risk of cardiovascular disease. We present the case of one of the oldest living patients with HoFH. Case Description: The patient is a 67-year-old black woman diagnosed with corneal arcus senilis and xanthomas at the age of 11, with total cholesterol (TC) levels &amp;gt;1000 mg/dL. At age 12, she underwent a partial ileal bypass (PIB) that lowered her TC by 39%. At age 32, she began statin therapy (Lovastatin, intensified to Atorvastatin at age 43). Despite concomitant dietary changes, her LDL levels remained elevated (&amp;gt;400 mg/dL). At age 34, multivessel coronary artery disease was detected and she initiated lipoprotein apheresis. Her LDL-C was reasonably well-controlled over the 20 years on LDL apheresis and high intensity statin therapy. Combined therapy with PCSK9 inhibitors (Evolocumab at age 61, replaced by Alirocumab at age 67) and ANGPTL3 inhibitor Evinacumab (age 67) lowered her LDL-C significantly. Genetic analysis confirmed two LDLR mutations: c.1846-1G&amp;gt;A and c.907C&amp;gt;T. Conclusion: Elevated cholesterol levels are linked to a higher risk of premature myocardial infarction and stroke. We report a case of HoFH with successful lowering of LDL levels on dual antibody and high intensity statin therapy along with PIB. Unlike PCSK9 inhibitors, ANGPTL3 inhibitors work independently of LDLRs by stimulating lipoprotein &amp; endothelial lipase. This case offers insight into early surgical and combination drug therapy in HoFH and describes one of the longest living patients with HoFH illustrating treatment evolution.
Abstract 10202: DNA-PKcs: A Novel Therapeutic Target in Pulmonary Arterial Hypertension
Authors: Keiko Yamamoto, Tetsuro Yokokawa, Sarah-Eve Lemay, Alice Bourgeois, Tsukasa Shimauchi, Kana Shimauchi, Valerie Nadeau, MABROUKA SALEM, Sandra Breuils Bonnet, francois potus, Olivier Boucherat, Steeve Provencher, Sebastien Bonnet
Journal: Circulation (2022)

Introduction: Pulmonary arterial hypertension (PAH) is a progressive disease characterized by vascular obliteration of small pulmonary arteries (PAs), notably due to excessive proliferation and resistance to apoptosis of pulmonary artery smooth muscle cells (PASMCs). Accumulating evidence indicates that PAH-PASMCs have acquired an over-efficient DNA damage response (DDR) ensuring sensing, signaling, and repair of DNA damages, accounting for their enhanced capacity to survive and proliferate under stressful conditions. DNA-dependent protein kinase (DNA-PK) is a pivotal component of the DNA repair machinery which plays an instrumental role in the overall survival and proliferation of cancer cells. Based on similarities between PAH and cancer cells, we thus hypothesized that increased expression of DNA-PK contributes to vascular remodeling in PAH. Methods and Results: Using Western blot (WB) and immunohistochemistry, we found that expression and activity of DNA-PK were increased in PAH-PASMCs (n=6) compared to controls (n=6, p&lt;0.01). Similarly, DNA-PK was significantly up-regulated in distal PAs from PAH animal models (i.e. MCT rats and Su/Hx rats and mice, n=5/group, p&lt;0.01). In vitro, the pharmacological inhibition of DNA-PK using AZD-7648 or Nedisertib attenuates PAH-PASMC proliferation (Ki67 and EdU labeling, MCM2, PLK1, and PNCA by WB; p&lt;0.05) and resistance to apoptosis (AnnexinV labeling, Survivin by WB)(n=5 cell lines; p&lt;0.05). These effects were associated with reduced expression of gH2AX. As assessed by echocardiography and right heart catheterization, treatment with AZD7648 improved pulmonary hemodynamics (RVSP, mPAP, and TPR) and right ventricular function (CO, PAT/PET, TAPSE) in Su/Hx mice with established PAH (n=10/group; all p&lt;0.01). Accordingly, pulmonary vascular remodeling (EVG) and the proportion of PCNA-positive PASMCs were reduced in AZD7648-treated Su/Hx mice when compared to vehicle-treated Su/Hx mice (p&lt;0.001). Conclusions: We showed for the first time that DNA-PK is overexpressed in human and experimental PAH and contributes to the pro-proliferative and anti-apoptotic phenotype of PAH-PASMCs.
Abstract 10848: Adar1 Mediated Rna Editing Contributes to Vascular Remodeling
Authors: Hyunbum Kim, Yu Liu, Timothy Klouda, Valerie A Schumacher, Alfred A Thompson, Joseph C Wu, Jin Billy Li, Benjamin Raby, Ke Yuan
Journal: Circulation (2022)

Intro: Adenosine deaminases acting on RNA 1 (ADAR1) catalyzes the conversion of adenosine (A) to inosine (I) on RNA transcripts. Due to the host immune response to non-edited double-stranded RNAs, ADAR1 deficiency has been linked to spontaneous type I interferon (IFN) signaling. Few studies have examined the role of RNA editing in vascular remodeling-associated diseases, including pulmonary arterial hypertension (PAH), a devastating disease that can lead to right heart failure and premature death. Hypothesis: ADAR1 mediated RNA editing plays a vital role in vascular diseases, particularly the pathogenesis of PAH. Methods and Results: Deeply sequenced RNA-seq data analysis using the SOAP2 program showed that IPAH patient smooth muscle cells (SMCs, N=3) have shown significantly fewer editing sites in transcripts than healthy SMCs (N=3) &amp; decreased levels of ADAR1 mRNA and protein. ADAR1 knockdown in healthy donor SMCs resulted in increased proliferation, migration and contractility, along with upregulated expression of IFN-b signaling-related molecules, such as MDA5 and ISG15. Furthermore, overexpression of MDA5, a dsRNA sensor of ADAR1-mediated immune response, in healthy SMCs induced activation of IFN-b signaling. A novel transgenic mouse model (ADAR1 SMC-KO ) was generated by knocking down ADAR1 (ADAR1 fl/fl ) selectively in smooth muscle actin-positive SMCs (SMA-CreER). Compared to controls, ADAR1 SMC-KO mice that underwent 3wk hypoxia developed severe pulmonary hypertension as evidenced by high RVSP (37mmHg, Fig1A) &amp; RVH(FI: 42%, Fig1B) with the excessive vascular remodeling in distal vessels. They also expressed higher expression of IFN-b in serum and increased recruitment of inflammatory cells, including macrophages and monocytes(Fig1C). Conclusions: This study reveals a novel molecular mechanism of ADAR1 contributing to abnormal vascular remodeling mediated by upregulation of Type 1 IFN-b, which could be central to the pathobiology of PAH.
Abstract 10530: Incidence and Electrocardiographic Predictors of Atrioventricular Conduction Recovery After Permanent Pacemaker Implantation in Transcatheter Aortic Valve Replacement
Authors: Zekun Feng, Ho-hin Choy, Soomin Shin, Andrew Vu, Amir Schricker, Richard Hongo, David Daniels, Christopher E Woods
Journal: Circulation (2022)

Background: High grade atrioventricular (AV) block (HGAVB) after transcatheter aortic valve replacement (TAVR) requiring permanent pacemaker implantation (PPM) is a well-established complication, but recovery of intrinsic AV conduction is not well studied. We assessed the incidence and electrocardiography (ECG) predictors of AV conduction recovery after PPM implantation post-TAVR. Methods: In this multicenter, retrospective study, consecutive patients undergoing TAVR between January 2015 to February 2019 were identified. All patients requiring PPM for HGAVB within 30 days after TAVR were included. Follow up ECGs, PPM checks, and clinic notes were reviewed to determine AV conduction recovery, defined as no need for ventricular pacing. Results: There were 533 TAVR patients, 443 with balloon expandable valves (BEV) and 90 with self-expanding valves (SEV). 5.1% of patients (n=27) required PPM for HGAVB, including 4.5% (n=20) from BEV group and 7.8% (n=7) from SEV group. Right bundle branch block (RBBB) was the most common baseline ECG finding (n=19). Mean time to PPM implant was 3.3±4.5 days. 11 patients received leadless and 16 received conventional pacemakers. At 6 months, 65% (n=13) of BEV group and none of SEV group had AV conduction recovery. BEV patients without AV conduction recovery had significantly longer baseline PR intervals compared to those with recovery (248±85 msec vs 169±22 msec; 95% CI 12.5-147.2; p=0.024). There were no significant differences in baseline QRS duration or presence of RBBB between those with and without AV conduction recovery. Conclusion: AV conduction recovery is more frequent after PPM implantation in TAVR patients receiving BEV (65%) compared to SEV (0%). Normal baseline PR intervals at baseline is associated with higher rate of AV conduction recovery among BEV patients. Temporary pacing with leadless pacemakers may be an alternative to conventional pacemakers in BEV patients without baseline first degree AV block.
Abstract 10309: Susceptibility-Weighted Imaging is Not Inferior to CT in Detecting Intracranial Vertebral Artery Calcification
Authors: Hon-Man Liu
Journal: Circulation (2022)

Susceptibility-Weighted Imaging is not inferior to CT in detecting intracranial vertebral artery calcification Hon-Man Liu. Department of Medical Imaging, Fu-Jen Catholic University Hospital, Fu-Jen Catholic University, New Taipei City, Taiwan Introduction: Microcalcification is vulnerable and ready to rupture, and macrocalcification is more stable. CT is more sensitive to detect calcification than conventional MR. We demonstrated that the advance MR technique, susceptibility-weighted imaging (SWI), is not inferior to CT in detecting calcification of intracranial vertebral artery. Hypothesis: Susceptibility-weighted imaging can detect paramagnetic blood clots and diamagnetic calcification. Materials and methods: We reviewed the patients’ brain SWI imaging between January 2021 to March 2022 in our institute. The inclusion criteria were patients had SWI and brain CT done within 3 months. The exclusion criteria were poor imaging quality, insufficient study, and incomplete study. We defined that vessel wall calcification as void signal on SWI and hyper-attenuation (&gt; or =100 HU) on CT. We compared the incidence and location of the calcification shown on CT and the void signal on SWI in the intracranial vertebral artery wall. Results: A total of 817 patients is eligible for this study. They were aged between 25 years to 90 years old and 393 were females. A 3.0T MR scanner was used in 486 patients, and 1.5T in 331. On CT, intracranial vertebral artery calcification was shown in 613 vertebral arteries. Susceptibility-weighted imaging could depict 98.5% (n=604) void signal at the corresponding intracranial vertebral artery segment shown on CT. Void signal on SWI is conspicuous in 12 foci that not shown as hyper-attenuation on CT. Conclusion: Susceptibility-weighted imaging is not inferior to CT in detecting intracranial vertebral artery calcification. SWI can play a role in the research about intracranial atherosclerosis in the future.
Abstract 10403: Residual Lesion Severity is Associated With Adverse Neurodevelopmental Outcomes in Young Children With Congenital Heart Disease
Authors: Aditya Sengupta, Kimberlee Gauvreau, Anjali Sadhwani, SAMANTHA C BUTLER, Jane W Newburger, Pedro J Del Nido, Meena Nathan
Journal: Circulation (2022)

Introduction: There are few modifiable risk factors for adverse neurodevelopmental (ND) outcomes in congenital heart disease. We assessed the Residual Lesion Score (RLS), a quality improvement metric that assesses residual lesion severity following congenital heart surgery (CHS), as a predictor of ND delay. Hypothesis: We hypothesized that RLS would be independently associated with ND outcomes. Methods: This was a single center, retrospective review of patients who underwent CHS from 01/2011-12/2019 and received post-discharge ND evaluation between the ages of 12 and 42 months using the Bayley Scales of Infant Development, 3 rd ed. (BSID-3). RLS was assigned at discharge per previously published criteria: Class 1, no residua; Class 2, minor residua; Class 3, major residua or in-hospital unplanned reintervention. Associations between RLS and BSID-3 scores (at the first ND evaluation) were evaluated using linear regression, adjusting for baseline patient risk, the Childhood Opportunity Index, and maternal education level. Linear mixed effects models assessed trends in ND outcomes over time. Results: Of 477 patients with mean age at ND testing of 21.2 ± 6.1 months, 282 (59.1%), 132 (27.7%), and 63 (13.2%) patients had RLS 1, 2, and 3 lesions, respectively. Table 1A shows BSID-3 outcomes by RLS. On multivariable analysis, Class 3 patients had significantly lower cognitive, receptive and expressive communication, and fine and gross motor scaled scores, compared to Class 1 patients, with the largest difference observed in the cognitive domain ( Table 1B ). In a subset of 191 patients with more than one ND evaluation, Class 3 patients made fewer gains in skills from the first to the last evaluation in the cognitive and language domains, compared to Class 1 patients (both p&lt;0.05). Conclusions: Patients with major residua (RLS 3) are at increased risk for ND delay, warranting closer ND follow-up and greater developmental support for cognitive, communication, and motor skills.
Abstract 10487: In vivo Efficacy of HS135, a Novel Activin and GDF Trap for the Treatment of Pulmonary Hypertension (PH) and Metabolic Syndrome (MetS)
Authors: Gauthier Schang, Mathilde Poujol de Molliens, Jean-Francois Denis, Cristina Chauvet, Emilie Brule, Julia Schoelermann, Gilles Tremblay, Maureen O'Connor-McCourt
Journal: Circulation (2022)

Introduction: PH is a disorder characterized by remodeling of the pulmonary vasculature which causes increased pulmonary vascular resistance and ultimately right ventricular (RV) failure leading to death. MetS is a recognized risk factor for PH, particularly in patients suffering from PH associated with left-sided heart failure (WHO Group 2 PH) for which there are no approved therapies. Activins and growth differentiation factors (GDFs) are implicated in both PH pathology as well as body composition and metabolism by genetic disease association, preclinical, translational, and clinical evidence. HS135 is a rationally designed first-in-class activin-receptor (ActR)-based fusion protein that addresses both vascular remodeling and MetS in PH without affecting hematological parameters; hematological effects limit the dosing of other ActR-based agents. Methods: HS135’s ability to counteract vascular remodeling and heart failure in PH was assessed using a rat monocrotaline (MCT) model: a single dose of 60 mg/kg MCT was administered on Day 0 followed by 4 weeks of twice weekly treatment with either HS135 (1, 4, or 16 mg/kg) or vehicle. PH efficacy was assessed at end of study by echocardiography and histological readouts. HS135’s ability to improve body composition and metabolism was assessed in wild type mice by administering HS135 (1, 3, 10, 20, or 50 mg/kg) or vehicle twice weekly for 3 weeks. The effect of HS135 on hematological parameters was assessed by whole blood cell count in non-human primates (NHPs) 2 weeks following a single administration of HS135 at 3 or 30 mg/kg. Results: HS135 at 3 or 30 mg/kg did not lead to changes in hematological parameters in NHPs. Compared to vehicle, HS135 was effective at counteracting the MCT-induced PH phenotype in rats as evidenced by significant reductions in Fulton index and improved echocardiography parameters. In wild type mice, HS135 led to significant improvements in body composition. Conclusions: Contrary to other ActR-based therapies, HS135 did not lead to increases in hematocrit which would limit its dosing. HS135 was efficacious at treating PH while simultaneously improving body composition in preclinical models. Clinical trials with HS135 are expected to commence within 2023.
Abstract 10085: Troponin Release is Associated With Mortality and Poor Fluid Resuscitation in Patients With Sepsis
Authors: Zhiyuan Ma, Mahesh Krishnamurthy, Vivek Modi, David Allen, Jamshid Shirani
Journal: Circulation (2022)

Introduction: Septic patients are predisposed to myocardial injury manifested as cardiac troponin release (TnR). Prognostic significance and management implications of TnR in this setting has not been fully elucidated. We aimed to determine the impact of admission TnR and fluid resuscitation on outcomes of patients with sepsis admitted to intensive care units (ICU). Methods: A total of 24,778 patients with sepsis from eICU-CRD (n=11,992), MIMIC-III (n=6,638) and MIMIC-IV (n=6,148) databases were examined for mortality and 1-year survival by multivariable logistic, Cox regression analysis, or Kaplan-Meier survival analysis with overlap weighting adjustment, as well as generalized additive models for fluid resuscitation. Results: TnR on admission was associated with higher in-hospital mortality [adjusted odds ratios (aOR)=1.33; 95% confidence interval (CI)=1.23-1.43; p&lt; 0.001 in unweighted analysis and aOR=1.39; 95% CI=1.29-1.50; p&lt; 0.001 with overlap weighting]. One-year survival was lower in patients with admission TnR (Kaplan-Meier survival analysis; p=0.002). A trend was noted for association between admission TnR and 1-year mortality [aOR=1.16; 95% CI, 0.99-1.37; p = 0.067 in unweighted analysis] while the association was statistically significant after overlap weighting (aOR=1.25; 95% CI=1.06-1.47; p=0.008). We also found that patients with admission TnR were less likely to benefit from more liberal fluid resuscitation. Adequate fluid resuscitation within a range of 70 to 90 ml/kg in the first 24 hours of ICU stay was associated with lower in-hospital mortality in septic patients without TnR but not in those with admission TnR. Conclusions: Admission TnR was significantly associated with higher in-hospital mortality and worse 1-year survival among septic patients. Adequate fluid resuscitation improved in-hospital mortality in septic patients without but not with admission TnR.
Abstract 10400: The Characteristics and Outcomes of Heart Failure Associated With Methamphetamine Use
Authors: Beani Forst, Abdulbaril Olagunju, Bikash Bhattarai, Tyler Harwood, Ayman Fath, Michael White
Journal: Circulation (2022)

Introduction: Heart failure (HF) remains a significant cause of morbidity and mortality in the United States (US). Approximately 6.2 million adults in the United Status have HF and results in an estimated 13.4% of deaths annually. While the development of HF is linked to a variety of risk factors, the incidence and prevalence of methamphetamine-associated HF (HF-Meth) is rising secondary to the methamphetamine epidemic that is plaguing America. This study aims to compare the characteristics and outcomes of HF-Meth with other forms of HF. Methods: The discharge data of the National Inpatient Sample (NIS) from 2009 to 2014 were analyzed and records for HF hospitalization were identified using all ICD-9 codes for HF. These were further stratified based on meth use with the ICD-9 codes (304.40, 305.7, 969.72). We compared frequency of in-hospital mortality,incidence of cardiac arrhythmias, sudden cardiac death (SCD), rates of unemployment, and homelessness between patients with and without ICD-9 codes indicative of meth use. Percentage and chi-square-based P-values were reported. Results: Out of the 25,209,723 sampling weight-adjusted patients with ICD-9 codes indicative of HF, 58,359 (0.23%) had ICD codes indicative of Meth use. Relative to other patients with HF, HF-Meth experienced a lower in-hospital mortality rate (2.9 vs 5.0%, p &lt;0.001), had a higher incidence of cardiac arrhythmias (7.1 vs 5.9%, p &lt;0.001) and SCD (2.6 vs 1.8%, p &lt;0.001), a higher rate of unemployment (0.49 vs 0.03%, p &lt;0.001) and homelessness (6.1 vs 0.2%, p &lt;0.001). In addition, HF-Meth was associated with a higher rate of alcohol abuse (21.1 vs 2.9%, p &lt;0.001), cigarette smoking (73.8 vs 28.2%, p&lt;0.001) and essential hypertension (43.8 vs 40.3%, p &lt;0.001). Diabetes and hyperlipidemia were more prevalent in patients with other forms of HF (29.3 vs 43.44%, p &lt;0.001 and 0.26 vs 0.45%, p &lt;0.001 respectively). Conclusions: Patients with HF-Meth had a higher rate of cardiac arrhythmias, SCD, unemployment and homelessness. Additionally, they had a lower in-hospital mortality when compared with those not associated with meth use.
Abstract 10900: Implication of the Post-Translational Formation of Hypusine in Eif5a in Pulmonary Arterial Hypertension
Authors: Sarah-Eve Lemay, Yann Grobs, Tsukasa Shimauchi, Sandra Martineau, Sandra Breuils Bonnet, MABROUKA SALEM, Francois Potus, Steeve Provencher, Sebastien Bonnet, Olivier Boucherat
Journal: Circulation (2022)

Pulmonary Arterial Hypertension (PAH) is characterized by progressive pulmonary arteries (PAs) obstruction leading to heart failure and death. PA smooth muscle cells (PASMCs) of PAH patients display a “cancer-like” phenotype that contributes to PA remodeling. Eukaryotic translation initiation factor 5A (eIF5A) was shown to provide cancer cells with a competitive advantage by increasing translation of mRNAs with oncogenic proprieties, many of them containing proline/glycine-rich patterns. Strikingly, eIF5A is the only protein containing the unique, polyamine-derived amino acid hypusine, which is required for its function. Hypusine formation is catalyzed by the sequential actions of deoxyhypusine synthase (DHPS) and deoxyhypusine hydrolase (DOHH). We hypothesized that increased eiF5A Hyp in PAH-PASMCs is required to promote translational efficiency of a set of factors conferring a higher survival and fibroproliferative capacity, leading to pulmonary vascular remodeling. Data derived from a comparative proteomic analysis (LC-MSMS) between normal and PAH-PASMCs and confirmed by Western blot indicate that DHPS and DOHH are overexpressed in PAH-PASMCs compared to controls (p&lt;0.05). Consistently, both total and hypusinated forms of eIF5A were found up-regulated in dissected PAs and PASMCs from PAH patients and animal models (MCT and Su/Hx rats, p&lt;0.05). In vitro , inhibition of DHPS and DOHH, using GC7 and ciclopirox, respectively, significantly attenuates PAH-PASMCs survival and proliferation, (Annexin V; Ki67 labeling and EdU incorporation, p&lt;0.01). These effects were confirmed by a reduced expression eiF5A Hyp , MCM2, PCNA and Survivin (p&lt;0.01) and a downregulation of BRD4, EP300 and COL1, three factors implicated in PAH containing proline/glycine-rich patterns. In vivo , inhibition of DHPS using GC7 in MCT rats with established PAH improves hemodynamics (RVSP, mPAP, CO, p&lt;0.05) and vascular remodeling (EVG, p&lt;0.05). Furthermore, preliminary data indicate that smooth muscle cells-targeted inactivation of one allele of Dhps tends to confer protection against Su/Hx-induced PAH in mice. We showed for the first time that hypusine signaling is implicated in PAH development and represents a new promising therapeutic target.